Quaternary salts of normorphine and its acylated derivatives



United States. Patent 3,101,339 QUATEARY SALTS-0F NORMORPHWE AND ITSACYLATED DERHVATHVES Karl Zeile and Kurt Freter, llngelheim, Germany,assignors to C. H. Boehringer Sohn, Ingelheim (Rhine), Germany, apartnership No Drawing. Filed Oct. 26, 1959, $1211. No. 858,556 Claimspriority, application Germany Oct. 3t}, 1958- 5 Claims. (Cl. 260-285) 1This invention relates to new, therapeutically active quaternary saltsof normorphine and of diacylated normor-phine derivatives.

More particularly, the present invention relates to norrno-rphiniumcompounds having the structural formula R O R 1 1 R2 CH CH2 R0 X or)wherein R is selected from the gnoup consisting of :acyl and hyd-rogen,

X is selected from the group consisting of chlorine,

bromine and iodine, and

R and R are selected from the group consisting of propyl,

,al-lyl and propargyl.

The compounds having the structural Formula I above may mostconveniently be prepared by reacting a normorphine compound of theformula wherein R is hydrogen or .a lower acyl radical and R and R arepropyl, allyl or propargyl radicals, with a halide of the formula R X(Ill) RZX (Illa) wherein R and R have the meanings previously definedand X is a halogen selected from the group consisting of chlorine,bromine and iodine.

More particularly, the reaction between the compound of the Formula IIor 111a and the halide or" the Formula. III or llla may be carried outin the presence of an inert solvent or without a solvent and at roomtemperature or elevated temperatures. at elevated temperatures it isadvantageous to let it proceed at the boiling point of the reactionmixture. The presence of an excess of the halide reaction component isalways necessary, and if the reaction is carried out without a solventthe halide should be present in an amount of 10 to 15 times by weight ofthe normorphine compound II or Ha. The yield of purified reactionproduct is from 60 to of theory.

if radicals R and R in Formula I are to be different, a reversal of thesequence of introduction of radicals R or R leads to stereoisomericforms of compound I. F or example, the reaction ofN-propargylnormorphine with allyl bromide as well as the reaction ofN-allyl-normorphine with propargyl bromide yield quaternary salts whichdo not difier from each other either in their melting points or in theiroptical rotation values. A mixture of the reaction products of these tworeactions does not exhibit a depression of the melting points of eitherof the reaction products alone. However, the two stereoisomers differfrom each other in their characteristic bands of the infrared spectrum.

The following examples will illustrate the present inven" rtion andenable others skilled in the :art to understand it more completely.However, it is to be understood that the invention is not limited tothese illustrative examples.

. EXAMPLE I N-Diallyl-Normlorphinim'um Bromide 20 gm.N-allyl-normorphine and 300 gm. allyl bromide were refluxed for 12hours, accompanied by stirring. The reaction mixture was then allowed tocool, the precipitate formed thereby was separated on a vacuum filterand the filter cake was washed with ether. The raw reaction product wasobtained with a virtually quantitative yield. The raw product wasrecrystallized from boiling alcohol by adding chlorofiorm. The purifiedproduct was iound to have the structural formula I CHzCH=OH2 lCH --CH2HO Er and a melting point of C. (decomposition). The yield was 21 gm,which is 75% of theory. [It was readily soluble in water.

EXAMPLE II N -Diallyl-N0rm 0rphinium: Iodide 20 gm. N-allyl-normorphinewere dissolved in 200 cc. chloroform. 50 gm. allyl iodide were added tothe resulting solution, and the mixture was allowed to stand at roomtemperature. A iter ea fiew hours of standing a precipitate formed whichwas separated from the reaction mixture and purified as described inExample I. The purified product was found to have the structural formulaIf the reaction is carried out and a melting point of 164 C. The yieldwas 18 gm, which is 50% of theory.

EXAMPLE III Diacetyl-N-Diallyl-Normorphiniwm Bromide A mixture of 20diacetyl-N-allyl-normorphine and 200 gm. allyl bromide was heated at 70C. for 12 hours. The precipitate formed thereby was separated from thereaction mixture and was then recrystallized from chloroform. Theproduct was found to be practically .purediacetyl-N-diallyl-normorphinimum bromide of the for mula having amelting point of 18 8" C. The yield was 21 gm., which is 80% of theory.

EXAMPLE IV Dipropionyl-N-Diallyl-Normorphinium Bromide A mixture of 20gm. dipropicnyl-N-allyl-normorphine and 200 gm. allyl bromide was heatedand thereafter worked up as described in Example Ill. Analysis of thepurified product showed that it had the structural formula and a meltingpoint of 190 to 193 C. The yield was 80% .of theory.

EXAMPLE V N -Prpargyl-N-A Zlyl-N orm rphinium Bromide A mixture of gm.N-pnopargyl-normorphine and 200 'gm. 'al-lyl bromide (weight ratio 1:10)was refluxed for 12 hours. Some of the reaction product precipitated outduring refluxing, but the precipitation was brought to completion .bycooling the reaction mixture subsequent to the refluxing period. Theprecipitate was separated by vacuum filtration and was thenrecrystallized from water. The purified reaction product was found tohave the structural formula CHr-CECH 6B CH2-OH=OH2 CH -CH: 110

a melting point of 185 to 186 C. (decomposition), an optical rotation[a] =99 i1 (c.=1%, methanol) and a molecular weight of 430.1.

EXAMPLE VI N -Dipr0pargyl-N ormorphinium Bromide A mixture of 20 gm.N-propargyl-normorphine and gm. propargyl bromide (Weight ratio 1:8) wasrefluxed in 300 gm. acetone and worked up as described in Example V. Thereaction product was found to have the structural formula l GHQ-CECE CHH2 and a melting point of 182 C. (recrystallized from water). Itsmolecular weight was 428.1.

Calculated: N, 3.3%; Er, 18.6%. Found: N, 3.1%; Br, 19.0%.

EXAMPLE VII 3,6-Diacetyl-N-Propyl-N-Allyl-Normorphinium Bromide Amixture of 20 gm. diacetyl-N-propyl-normorphine and 200 gm. allylbromide was refluxed and Worked up as described in Example V, exceptthat the raw reaction product was recrystallized from a mixture ofchloroform and ether (1:1). The purified reaction product was found tohave the structural fomula O i CHr-CHECHZ I CH -CH2 CH2CO and a meltingpoint of C.

Analysis: C H O NBr, H O; mol. wt. 536.3. Calcu lated: C, 58.2%; H,6.3%; N, 2.6%. Found: C, 57.7% H, 6.6%; N, 2.6%.

EXAMPLE VIII N-Fropargyl-N-Propyl-Normorphinium Bromide A mixture of 20gm. N-propyl-normorphine and 200 gm propargyl bromide (weight ratio 1:10) in 200 gm. acetonr was refluxed for 16 hours. The reaction mixturewa: then allowed to cool, the precipitate formed thereby wa: separatedon a vacuum'filter, the filter cake was washec with ether andrecrystallized from water. The purifie reaction product was found tohave the structural formulz N-Dipropyl-Normorphinium Iodide A mixture of20 gm. N-propyl normorphine and 200 gm. propyl iodide was refluxed asdescribed in Example VIII, and the raw reaction product wasrecrystallized from alcohol/ether. The purified product was found tohave the structural formula and a melting point of 17 2 to 179 C.(decomposition).

EXAMPLE X N- Diallyl-Normorphinium Chloride 'A mixture of 1 part byweight N-allyl-noimorphine', parts by weight acetone and 10 parts byweight allyl chloridewas boiled tor 24 hours. The reaction mixture wascooled and the precipitate formed thereby was separated by vacuumfiltration, washed with ether and recrystallized from water. Thepurified reaction product was found to have the structural formula and amelting point of 179 C.

EXAMPLE XI 3,6-Diacetyl-N-Propyl-N-Propargyl- N ormorphinium Bromide Amixture of 10 gm. diacetyl-N-propyl-normorphine and 200 gm.propargyl-bromide was boiled for .6 hours. The reaction mixture was thencooled and introduced into six times its Weight of ether. A precipitateformed which was separated and recrystallized from water. The purifiedreaction product was found to have the structural formula and a meltingpoint of to C. (decomposition). The compounds embraced by formula Iabove have unexpected and useful pharmacological properties; moreparticularly, they are highly efiective antagonists against theanalgesic action of morphine and, when administered alone, they act asanalgesics.

It is known that N allyl-normorphine has an antagonistic efiect againstthe analgesic activity of morphine, and that by itself it exhibitsanalgesic acitvity. However, the practical use of N-allyl-norrnorphineas a pharmacological agent is seriously restricted by the numerous sideefiects which it produces, such as rest-lesness, nausea andhallucinations. I

The compounds according to the present invention are not only much moreeffective morphine antagonists but in addition do not produce anyundesirable side ef-' fects of any kind.

'1 o demonstrate the more efiective antagonistic activity of thecompounds disclosed herein against the analgesic effect of morphine,[the following comparative tests were made:'

A given number of mice were divided intotwo groups comprising an equalnumber of mice. The mice of the first group were given subcutaneousinjections of solutions containing varying quantities of morphine and N-allyl-normorphine. After each injection each mouse was examined by themethod of Haifner, Dentsche Medizinische Wochenschrift .54, 731' (1929),to determine the presence of detectableanalgesia. The mice of the secondgroup were treated and examined in anal ogousiashion,

except that the injected solution contained varying amounts of morphineand N-diallyl-normorphinium bromide.

The tollowing table shows the results of these comparatit 1e tests. Theleft-hand column indicates the amounts of morphine andN-allyl-normorphine or N-dia'llylnormorphinium bromide in the injectedsolutions, and the right-hand column indicates, in percentage terms, thenumber of mice in which the presence of detectable analgesia was t'ound.

subcutaneously injected mixture:

Portion of treated mice with detectable analgesia,

15 mg/kg. morphine+15 mg./kg.

N-diallyl-normorphinium bromide 0 20 m:g./kg. morphine-[-20 m g./kg.

N diallyl-normorphinium bromide 0 The results of these tests tabulatedabove clearly showed that the representative compound according to thepresent invention is by far more effective as antagonist against theanalgesic action of morphine than -N-a1lyl-normorphine.

For therapeutic administration in dosage form the compounds embraced byFormula I above may be compounded With suitable non-toxic, inert liquidor solid pharmaceutical carriers to produce ampules, tablets and thelike. The tollowing examples illustrate the composition of typicalpharmaceutical preparations suitable for administration of the compoundsin dosage form.

EXAMPLE XII Ampules The eifective single dosage of the compounds inhuman therapy is 20 to 120 mg, and preferably 40 to 100 mg.

While We have illustrated the present invention with the aid of specificrepresentative embodiments, it will be apparent to those skilled in theant that the present invention is not limited to those embodiments andthat various changes and modifications may be made without departingirom the spirit of the invention or the scope of the appended claims.

We claim:

1. N-substituted normorphi-nium compounds having the structural formula-N l i Rz on -GH2 RO- X9 wherein R is selected from the group consistingof hydrogen and lower alkanoyl,

R and R are selected from the group consisting of propyl, allyl andpropangyl, and

X is selected ctrom the group consisting of ohlorine,

bromine and iodine. 2. Nadiallyl-normorphinium bromide. 3.Diacetyl-N-diallyl-normorphinium buomide. 4.N-propaugyl-N-allyl-nonmorphinium bromide. 5.N-dipropangyl-normorphinium bromide.

References Cited in the file .of this patent UNITED STATES PATENTS2,364,833 Weijland et al. Dec. 12, 1944 2,619,485 Ohabrier et a1. Nov.25, 1952 2,741,609 Weijland Apr. 10, 1956 2,928,768 Freedman et a1. Mar.15, 1960 2,967,130 Sanders et a1. Jan. 3, 1961 FOREIGN PATENTS 755,521Great Britain Aug. 22, 1956 OTHER REFERENCES Braun: Berichlte, volume49, page 987 (1916).

Winter et 211.: Archives Internationales :de Pharmacodynamie et all.Therapie, volume 110, pages 186-200 (1957).

1. N-SUBSTITUTED NORMORPHINIUM COMPOUNDS HAVING THE STRUCTURE FORMULA